U.S. patent application number 10/518909 was filed with the patent office on 2006-01-19 for novel floating dosage form.
Invention is credited to Braj Bhushan Lohray, Pavak R. Mehta, Krishna T. Murthy, RaveendraM Pai, Sandip B. Tiwari.
Application Number | 20060013876 10/518909 |
Document ID | / |
Family ID | 29798520 |
Filed Date | 2006-01-19 |
United States Patent
Application |
20060013876 |
Kind Code |
A1 |
Lohray; Braj Bhushan ; et
al. |
January 19, 2006 |
Novel floating dosage form
Abstract
Present invention relates to a novel pharmaceutical composition
containing an active ingredient(s) which is retained in the stomach
or upper part of gastrointestinal tract for controlled delivery of
medicament for improved local treatment, and/or better absorption
from upper parts of gastrointestinal tract for effective
therapeutic results. Present invention also provides a method for
preparation of the said dosage form preferably in the form of a
bilayer tablet, in which one layer constitutes for spatial control
and the other being for temporal control.
Inventors: |
Lohray; Braj Bhushan;
(Gujarat, IN) ; Tiwari; Sandip B.; (Gujarat,
IN) ; Pai; RaveendraM; (Gujarat, IN) ; Murthy;
Krishna T.; (Gujarat, IN) ; Mehta; Pavak R.;
(Gujarat, IN) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Family ID: |
29798520 |
Appl. No.: |
10/518909 |
Filed: |
June 25, 2003 |
PCT Filed: |
June 25, 2003 |
PCT NO: |
PCT/IN03/00229 |
371 Date: |
September 1, 2005 |
Current U.S.
Class: |
424/472 |
Current CPC
Class: |
A61K 9/0065
20130101 |
Class at
Publication: |
424/472 |
International
Class: |
A61K 9/24 20060101
A61K009/24 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 26, 2002 |
IN |
565/MUM/2002 |
Claims
1. A pharmaceutical gastro-retentive delivery system for controlled
release of therapeutically active agent in stomach or upper part of
gastrointestinal tract in the form of bilayer dosage form which
comprises, a) a first layer (layer-A) which is responsible for
retaining the dosage form in stomach or upper part of
gastrointestinal tract (spatial control) for a prolonged period,
comprising of pharmaceutical excipients having low bulk density,
selected from a mixture consisting of (i) polymers selected from
ethylcellulose or suitable enteric polymers of cellulose
derivatives and (ii) hydrogenated oils, waxes, fatty acids either
alone or in combination; optionally with other pharmaceutical aids;
b) a second layer (Layer-B) which is responsible for prolonged or
controlled drug delivery (temporal control) of therapeutic agent
which comprises of the active agent and controlled release matrix
polymers optionally with other pharmaceutical aids.
2. The delivery system as claimed in claim 1 wherein said
pharmaceutical excipient with low bulk density is ethyl cellulose
in combination with hydrogenated oils.
3. The delivery system as claimed in claim 1 wherein the ratio of
ethylcellulose and hydrogenated oils is in the range of 95:5 to
30:70.
4. The delivery system as claimed in claim 1 wherein said
pharmaceutical aids are selected from pharmaceutical lubricants,
antiadherents and glidants.
5. The delivery system as claimed in claim 4, wherein said
pharmaceutical aids are selected from magnesium stearate, talc,
colloidal silicon dioxide, stearic acid, magnesium stearate
flimerate, glyceryl behenate and hydrogenated oils or combination
thereof
6. The delivery system as claimed in claim 1 wherein said
controlled release matrix polymers is selected from synthetic or
semisynthetic cellulose derivatives like hydroxypropyl
methylcellulose, ethylcellulose, hydroxypropylcellulose,
methylcellulose, sodium carboxymethylcellulose, natural polymers
such as xanthan gum, gelatin, synthetic polymers, acrylic acid
derivatives and polyvinyl acetate or mixtures thereof.
7. The delivery system as claimed in claim 1 wherein said
pharmaceutical aids are selected from group of pharmaceutical
fillers, disintegrants, lubricants, binders, antiadherents and
glidants or combinations thereof.
8. The delivery system as claimed in claim 7 wherein said,
pharmaceutical disintegrants are selected from crosslinked
polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose,
sodium starch glycolate, microcrystalline cellulose, starch, and
pregelatinized starch or their combinations.
9. The delivery system as claimed in claim 7 wherein said
pharmaceutical binders are selected from natural polymers selected
from starch or gum including acacia, tragacanth, gelatin or
synthetic polymers selected from polyvinyl pyrrolidone, methyl
cellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose, hydroxypropyl cellulose.
10. The delivery system as claimed in claim 7 wherein said
pharmaceutical antiadherents, glidants and lubricants are selected
from magnesium stearate, talc, colloidal silicon dioxide, stearic
acid, salts of stearic acid, magnesium stearate flimarate, glyceryl
behenate and hydrogenated oils.
11. The delivery system as claimed in claim 1, wherein said
therapeutically active agent is in the form of a raw powder,
dispersed or embedded in a suitable liquid, semisolid, micro- or
nanoparticles, micro- or nanospheres, a tablet, a caplet, or in a
suitable processable form.
12. The delivery system as claimed in claim 1, wherein said
therapeutically active agent is a drug having a narrow absorption
window in the gastrointestinal tract.
13. The delivery system as claimed in claim 1, wherein said
therapeutically active agent is selected from the group consisting
of therapeutic, chemotherapeutic, antibiotic antidiabetic,
anti-cancers, anti-Fungals, anti-filarial, antiviral agents, lipid
lowering agents, analgesics, non-steroidal anti-inflammatory
agents, anti-ulcer agents, anti-epileptics, anti-gout,
immunosuppressants, drugs for respiratory therapy, dopaminergic
agents, skeletal muscle relaxants, cardiovascular agents,
antipsychotics or those drugs which does not show uniform
absorption characteristic throughout the length of the
gastrointestinal tract.
14. The delivery system as claimed in claim 1, wherein said
therapeutically active agent may also be a drug for local treatment
of the gastrointestinal tract.
15. The delivery system as claimed in claim 1, wherein said
therapeutically active agent is selected from
antibacterial/anti-infective agents, such as ofloxacin,
ciprofloxacin, cefiroxime, cefatrizine, cefpodoxime,
clarithromycin, loracarbef, azithromycin, cefadroxil, cefixime,
amoxycillin; antivirals, such as acyclovir; cardiovascular agents,
such as diltiazem, captopril; lipid lowering agents such as
si.mvastatin, lovastatin, atorvastatin; non-steroidal
anti-inflammatory agents such as etodolac, ketorolac; anti-ulcer
agents such as ranitidine, famotidine; drugs for respiratory
diseases, such as fexofenadine, pseudoephedrine,
phenylpropanolamine, dextromethorphan, chlorpheniramine;
dopaminergic agents, such as bromocriptine; immunosuppressants,
such as cyclosporin; skeletal muscle relaxants, such as baclofen;
anti-gout agents, such as allopurinol; antidiabetic agents such as
acarbose, glipizide.
16. Use of the delivery system as claimed in claim 1, for treatment
of disease conditions as described in any preceding claims
above.
17. The delivery system as claimed in claim 1 wherein the layers A
& B are prepared by technique selected from melt granulation,
wet granulation or direct compression.
18. The delivery system as claimed in claim 1 wherein the amount of
therapeutically active agent is present in an amount ranging from
about 0.2 to 1000 mg.
19. The delivery system as claimed in 1 wherein the dosage form
floats on the surface of the gastric fluid for prolonged period
ranging from 0.5 to 10 hours.
20. The delivery system as claimed in claim 1 which is optionally
coated with rapidly dissolving water soluble film forming polymer
or rapidly dissolving pharmaceutical excipient.
21. A drug delivery system as claimed in claim 1 which includes
tablets, caplets or tablets filled in capsules.
22. A pharmaceutical composition prepared according to the present
invention suitable for human administration.
Description
FIELD OF INVENTION
[0001] Present invention relates to a novel pharmaceutical
composition containing an active ingredient(s) which is retained in
the stomach or upper part of gastrointestinal tract for controlled
delivery of medicament for improved local treatment, and/or better
absorption from upper parts of gastrointestinal tract for effective
therapeutic results. Present invention also provides a method for
preparation of the said dosage form preferably in the form of a
bilayer tablet, in which one layer constitutes for spatial control
and the other being for temporal control.
BACKGROUND OF THE INVENTION
[0002] Oral administration of a drug is perhaps the least
predictable route of drug administration, yet it is the route that
is used most frequently. Oral medications such as tablets, capsules
etc. are relatively cheap to manufacture, offer convenient form of
drug administration and reduce the possibility of errors in total
dose if the patient is self administrating the dosage form.
Classically, oral medications are administered as immediate release
dosage forms. The major disadvantage of such immediate release
preparations is the repeated frequency of drug administration and
fluctuations in drug plasma levels. Use of oral controlled release
preparations circumvents these problems. Such type of drug delivery
systems are designed to deliver the drug in such a way that the
drug level is maintained within the therapeutic window and
effective and safe blood levels are maintained for a period as long
as the system continues to deliver the drug at a particular rate.
Controlled drug delivery usually results in substantially constant
blood levels of the active ingredient as compared to fluctuations
observed with immediate release dosage forms. Controlled drug
delivery results in optimum therapy, and not only reduces the
frequency of dosing, but may also reduce the severity of side
effects.
[0003] There are numerous advantages associated with the use of
controlled drug delivery systems. The main benefit in controlled
drug therapy is the improvement in efficiency of the treatment.
Controlled drug therapy reduces the required frequency of
administration, and single doses at periodic intervals are
sufficient, resulting in improved patient compliance.
[0004] A variety of controlled release dosage form designs has been
reported in literature. These controlled drug delivery systems are
based on different modes of operation and have been variously
named, for example, as dissolution controlled systems, diffusion
controlled systems, ion exchange resins, osmotically controlled
systems, erodable matrix systems, pH independent formulations,
swelling controlled systems and the like.
[0005] An ideal controlled drug delivery system should deliver the
drug at a constant rate as the system passes through the
gastrointestinal tract. In practice however it is bit difficult. An
orally administered drug delivery system encounters a wide range of
highly variable conditions such as pH, agitation intensity, and
composition of the gastrointestinal fluids as it passes down the
gastrointestinal tract. Various researchers have attempted to
design oral controlled drug delivery systems that overcome these
problems and deliver the drug at a constant rate as it passes down
the gastro-intestinal tract.
[0006] The absorption of the drug candidate from the
gastrointestinal tract is dictated by the location of the dosage
form in the gastrointestinal tract and the GI contents. Some drugs
are more efficiently absorbed from the upper part of GI tract while
others are absorbed from the lower parts of the gastro-intestinal
tract. Therefore, in instances where the drug is not absorbed
uniformly over the gastro-intestinal tract, the rate of drug
absorption may not be constant in spite of the drug delivery system
delivering the drug at a constant rate into the gastro-intestinal
fluids. In such cases where the drug has a particular absorption
site in the gastro-intestinal tract (i.e. absorption window),
stomach or upper part of the small intestine for example, the drug
may not be completely absorbed when administered in the form of a
typical controlled drug delivery system. It is clear that for such
drugs having an "absorption window" as stomach or upper parts of
small intestine, an effective oral controlled drug delivery system
should be designed not only to deliver the drug at a controlled
rate, but also to retain the drug in the upper parts of the
gastrointestinal tract for a long period of time.
[0007] WO 00/38650 describes composition for a pharmaceutical
dosage form for prolonged release of an active agent from a
multilayered dosage form having a highly swellable layer and a drug
layer, the dosage form being adapted for retention in the stomach
for a prolonged period. The dosage form upon contact with the
aqueous fluid/gastric contents swells to a maximum extent leading
to increased buoyancy of the dosage form and the whole dosage form
will float on the surface of the gastric contents.
[0008] U.S. Pat. No. 6,207,197 assigned to West Pharmaceutical
Services for Drug Delivery and Clinical Research Centre provides a
drug delivery composition for the controlled release of an active
agent in the stomach environment over a prolonged period of time.
This comprises of microspheres comprising an active ingredient in
the inner core of the microspheres and i) a rate controlling layer
of a water insoluble polymer and ii) an outer layer of a
bioadhesive agent in the form of a cationic polymer.
[0009] U.S. Pat. No. 5,780,057 assigned to Jagotec A G provides a
pharmaceutical dosage form for oral administration is a two- or
three-layered tablet, wherein at least one layer can rapidly swell
by contact with biological and/or aqueous fluids. The said swelling
results in a considerable increase in the tablet volume. This
phenomenon determines a prolonged residence of the pharmaceutical
form in the gastric mucosa and therefore allows slow release of the
active ingredient from said pharmaceutical dosage form to the
stomach and/or the upper part of the intestine.
[0010] U.S. Pat. No. 4,996,058 assigned to Ciba-Geigy corporation
relates to a covered, solid retard form which in the case of oral
administration remains in the stomach during periodic emptying and
ensures continuous release. This dosage form contains at least one
component that expands on contact with body fluid and contains a
physiologically active substance or a combination of such
substances. One permeable hydrophilic membrane which surrounds
component which is expansible at the site of use and optionally a
covering which surrounds components which, disintegrates without
delay under the action of body fluid at the site of use.
[0011] JP 06024959 assigned to Bayer Yakuhin KK discloses a
pharmaceutical composition to deliver the ciprofloxacin over a
prolonged period of time by making the tablet to suspend in the
stomach. The system contained two parts laminated to each other.
One part containing a water-swellable gel-forming polymer and a
water expandable foaming agent dispersed in the polymer and the
other part containing the active agent. The results showed that
only 46% of the drug was dissolved even after 24 hours loosing its
practicability to be effective as once daily ciprofloxacin
formulation.
[0012] U.S. Pat. Nos. 4,767,627, 4,735,804 and 4,758,436 present
dosage forms of various geometry; continuous solid stick;
tetrahedron; planar disc; multi-lobed flat device; and ring. The
devices are compressible to a size suitable for swallowing, and are
self-expandable to a size which prevents passage through the
pylorus. They are sufficiently resistant to forces of the stomach
to prevent rapid passage through the pylorus for a pre-determined
period of time and erode in the presence of gastric juices. The
devices are homogenous; they contain the same polymer constituents
in different areas of the device. The tetrahedron shape presented
in U.S. Pat. No. 4,735,804 is homogenous in its four lobes, which
are attached to each other by a polymeric matrix.
[0013] The medicaments are incorporated into the device as a liquid
solution or suspension, which may necessitate the addition of
mentioned preservatives or buffering agents. Alternatively, the
controlled release drug module may be tethered or glued to the
device.
[0014] WO 01/64183 assigned to Ranbaxy Laboratories describes a
pharmaceutical composition in the form of tablets or capsules which
provides a combination of spatial and temporal control of the drug
delivery, specifically for the drug ciprofloxacin. According to the
invention, the pharmaceutical composition is prepared by mixing the
drug with the gas generating component, the swelling agent, and one
or both of the viscolysing agent and the gelling agent, plus other
excipients and lubricants. The blend was either directly compressed
into tablets or may be filled into capsules. Alternatively, the
pharmaceutical composition is prepared by mixing the foregoing
ingredients with only one-half of the lubricants. The blend is
subjected to dry granulation technique by passing it through the
roller compactor and then sieved to obtain granules. The granules
are then mixed with the remaining lubricants, and filled into
capsules or compressed into tablets. The floating in the stomach is
achieved by interaction of the gas-generating component with the
gastric hydrochloric acid resulting in gas-entrapped gel matrix
having low density.
[0015] U.S. Pat. No. 3,574,820 describes the use of a gelatin
matrix that hydrates in the stomach, gels, swells and cross-links
with N-acetyl-homocysteine thiolactone to form a matrix too large
to pass through the pylorus.
[0016] U.S. Pat. No. 4,207,890 discloses a drug dispensing device
which comprises a collapsed, expandable imperforate envelope, made
of a non-hydratable, body fluid and drug-permeable polymeric film,
which contains the drug, and an expanding agent also contained
within the polymeric envelope which, when in contact with body
fluids, causes the envelope to expand to a volume such that the
device is retained in the stomach.
[0017] U.S. Pat. No. 4,434,153 describes a device comprised of a
matrix formed of a hydrogel that absorbs and imbibes fluid from the
stomach, expands and swells, in order to retain in the stomach for
an extended period of time, and a plurality of tiny pills dispersed
throughout the matrix, having a drug-containing core and a fatty
acid and wax wall surrounding the core. A significant disadvantage
of the devices of the above publications is that they appear to
ignore natural contractions of the stomach which may contribute to
a rapid diminishing of size, leading to early removal of the device
from the stomach. These devices lack the mechanical strength
required to withstand the natural mechanical activity, that
includes contractions of the stomach.
[0018] U.S. Pat. Nos. 5,002,772 and 5,443,843 disclose an oral drug
delivery system having a delayed gastrointestinal transit, which
releases the drug/s contained therein in a controlled manner and
which in their expanded form resist gastrointestinal transit. These
delivery systems comprise one or more retention arms as a
non-continuous compressible element, and an attached controlled
release drug-containing device. The preferred configuration is a
coil or a spiral. These systems must comprise at least two distinct
parts out of which at least one is retention arm and a controlled
release arm.
[0019] U.S. Pat. Nos. 5,047,464 and 5,217,712 describe a system
comprising bio-erodible, thermoset, covalently cross-linked, poly
(ortho) ester polymers, which expand from a compressed state upon
delivery thereof. The acidic environment of the stomach eventually
results in the degradation of the polymers within the system, thus
permitting its removal from the stomach. The system is
characterized by high resiliency.
[0020] U.S. Pat. No. 5,651,985 describes a system devised from a
mixture of polyvinyl-lactams and polyacrylates which are
characterized by their high degree of swelling in the stomach
resulting in its retention in the stomach for a prolonged period of
time.
[0021] U.S. patent publication No. 20030021845 describes a
gastroretentive drug delivery system comprising a single- or
multi-layered matrix comprising a polymer selected from degradable
polymers that may be hydrophilic polymers not instantly soluble in
gastric fluids, enteric polymers substantially insoluble at pH less
than 5.5 and/or hydrophobic polymers and mixtures thereof;
non-degradable polymers; and any mixtures thereof, a continuous or
non-continuous membrane comprising at least one polymer having a
substantial mechanical strength; and a drug; wherein the matrix
when affixed or attached to the membrane prevents evacuation from
the stomach of the delivery system for a period of time of from
about 3 to about 24 hours.
[0022] Not withstanding the above referenced prior information, the
present inventors have developed more simpler and possibly more
convenient dosage form preferably in the form of a bilayer tablet
or caplet, in which one layer constitutes for spatial control and
the other being for temporal control.
[0023] The present invention involves delivering the drug in the
form of a bilayer dosage form in which one layer constitutes for
spatial control and the other being for temporal control.
[0024] Spatial control layer comprises of low bulk density polymers
such as cellulosic derivatives either natural, synthetic or
semi-synthetic, ethyl cellulose in particular, polyethylene oxide,
fatty acids, hydrogenated oils, waxes, shellac, and the likes
either alone or in combination. Other optional pharmaceutical
excipients may also be incorporated. The temporal control layer
comprises of controlled release matrix polymers such as synthetic
or semisynthetic cellulose derivatives like hydroxypropyl
methylcellulose, ethylcellulose and the like and/or natural
polymers or gums such as xanthan gum, gelatin and the like, acrylic
acid derivatives, polyvinyl acetate along with other optional
pharmaceutical excipients. The active pharmaceutical ingredient is
incorporated into the temporal control layer. The temporal control
layer may also contribute to floating of the dosage form once the
system absorbs aqueous fluids from GI tract leading to swelling and
decrease in density. The final dosage form may be coated with
suitable coating materials for either functional or non-functional
use known to those in the art of formulation development.
OBJECTIVES OF THE PRESENT INVENTION
[0025] The objective of the present invention is to provide a novel
gastro-retentive delivery system for controlled release of
therapeutically active agent in stomach or upper part of
gastro-intestinal tract in the form of bilayer dosage form in
which; [0026] One layer (Layer-A) is responsible for retaining the
dosage form in stomach or upper part of gastro-intestinal tract
(spatial control) for prolonged period and is composed of
pharmaceutical excipients with low bulk density such as cellulosic
derivatives either natural, semi-synthetic or synthetic, ethyl
cellulose in particular, polyethylene oxide, fatty acids,
hydrogenated oils, waxes, shellac, and the likes either alone or in
combination and along with other optional pharmaceutical
excipients. [0027] The second layer (Layer-B) is responsible for
prolonged or controlled drug delivery (temporal control) and
comprises of controlled release matrix polymers such as synthetic
or semisynthetic cellulose derivatives like hydroxypropyl
methylcellulose, ethylcellulose and the like and/or natural
polymers or gums such as xanthan gum, gelatin, acrylic acid
derivatives, polyvinyl acetate and the like along with other
optional pharmaceutical excipients.
[0028] The dosage forms of the present invention can be a tablet or
caplet either coated or uncoated, or tablet filled in capsules.
[0029] Another objective of the present invention is to provide a
novel gastro-retentive delivery system for controlled release of
therapeutically active agent having absorption window and/or site
of action as stomach or upper parts of gastro-intestinal tract for
prophylactic and therapeutic use.
[0030] Still another objective of the present invention is to make
the dosage form float on the surface of the gastric contents with
controlled release of the active agent wherein the drug is
delivered over a period of time which is equal to or less than the
transit time of the dosage form in the absorptive region of the
gastrointestinal tract.
[0031] A further objective of the present invention is to release
the active pharmaceutical agent having absorption window as stomach
or upper part of gastro-intestinal tract in a slow, controlled
manner for better absorption and better efficacy compared to other
conventional and controlled release dosage forms.
[0032] Yet another objective of the present invention is to provide
a drug delivery system that can incorporate high and low dose
medicament without compromising dosage form
characteristics/properties with acceptable size for oral
administration.
DETAILED DESCRIPTION OF INVENTION
[0033] The present invention relates to a novel pharmaceutical
technology in the form of bilayer buoyant matrix dosage form to
prolong the delivery of the drug in the stomach or upper part of
small intestine. One layer makes the dosage form to stay/float on
the surface of the contents in the stomach giving spatial control
and the other layer containing the drug and controlled release
matrixing polymers optionally along with the other pharmaceutical
ingredients for temporal control of the drug.
[0034] According to the present invention, the novel technology
aims to retain the pharmaceutical dosage form in the stomach or
upper part of small intestine. This is achieved through a bilayered
pharmaceutical composition wherein one layer (Layer-A) is
responsible for spatial control by making the whole dosage form to
float on the surface of the aqueous/gastric contents of the
gastrointestinal tract and the other layer (Layer-B) comprising of
active pharmaceutical ingredient and controlled release matrixing
polymers along with optional pharmaceutical excipients, thereby
allowing prolonged release of the drug candidate.
[0035] In the present invention, the layer A which is responsible
for the buoyancy of the whole dosage form is composed of polymers
and/or suitable excipients whose density is below one because of
which the dosage form floats along with the other layer on the
surface of the gastric and/or aqueous media. In the present
invention the polymers used in the layer-A can be various
cellulosic derivatives either synthetic or semisynthetic, whose
density is less than one, preferably ethylcellulose, either alone
or in combination with pharmaceutical ingredients like,
hydrogenated oils, waxes, fatty acids, shellac, polyethylene-oxide
and the likes.
[0036] According to present invention the ratio between
ethylcellulose and hydrogenated oils for Layer A can vary from 95:5
to 30:70.
[0037] According to the present invention, the layer B contains the
active pharmaceutical ingredient along with, rate retarding
polymers, which may optionally be combined with fillers, binders,
superdisintegrating agents and other pharmaceutically acceptable
lubricants, glidants or anti adherents. The layer-B can be prepared
using various release rate retarding polymers such as cellulose
derivatives synthetic or semisynthetic like hydroxypropyl
methylcellulose, hydroxy ethylcellulose and the like and/or natural
polymers or gums such as xanthan gum, gelatin and/or polyethylene
oxide or other synthetic polymers such as acrylic acid derivatives,
polyvinyl acetate and the likes along with other optional
pharmaceutical excipients. The pharmaceutical composition may be
optionally coated with agents as is known in the art.
[0038] According to the present invention the drugs can belong to
any class and for any disorder by which the therapy or chemotherapy
would be improved as a result of controlled drug delivery. The drug
may be pharmacologically or chemotherapeutically active itself, or
may be converted into active species by a chemical or enzymatic
process in the body. Examples of suitable drugs candidates and
drugs used for different disorders, are antibiotics, anti-cancers,
anti-fungals, anti-fibrial and antiviral agents, lipid lowering
agents, non-steroidal anti-inflammatory agents, anti-ulcer agents,
drugs for respiratory therapy, dopaminergic agents, skeletal muscle
relaxants, cardiovascular agents, anti-epileptic,
immunosupressants, anti-gout, antipsychotics. Preferable drugs from
these classes are those whose absorption window and or site of
action is stomach or upper part of the small intestine and also
drugs which do not show uniform absorption characteristics
throughout the gastro-intestinal tract.
[0039] Illustrative examples of drugs that are suitable for the
present invention include antibacterial/anti-infective agents, such
as ofloxacin, ciprofloxacin, cefuroxime, cefatrizine, cefpodoxime,
clarithromycin, loracarbef, azithromycin, cefadroxil, cefixime,
amoxycillin and the like; antivirals, such as acyclovir;
cardiovascular agents, such as diltiazem, captopril, and the like;
lipid lowering agents such as simvastatin, lovastatin,
atorvastatin, and the like; non-steroidal anti-inflammatory agents
such as etodolac, ketorolac, and the like; anti-ulcer agents, such
as ranitidine, famotidine and the like; drugs for respiratory
diseases, such as fexofenadine, pseudoephedrine,
phenylpropanolamine, dextromethorphan, chlorpheniramine, and the
like; dopaminergic agents, such as bromocriptine;
immunosuppressants, such as cyclosporin; skeletal muscle relaxants,
such as baclofen: anti-gout agents, such as allopurinol: and the
like: antidiabetic agents such as acarbose, glipizide and the like.
The drug itself or its pharmaceutically acceptable salt or ester
may be used in the present invention. Moreover combinations of
drugs that are typically administered together may be included as
the drug component of the pharmaceutical composition. The amount of
drug to be used in the composition is that which is typically
administered for a given period of time. The drugs can be present
in the composition of about 0.2 to 1000 mg depending on the drug
candidate.
[0040] The release-retarding polymers used in the invention belong
to the class of cellulosics natural gums and/or acrylic acid
derivatives which may be either hydrophobic or hydrophilic. Release
retarding polymers may be selected from hydroxypropyl
methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium
carboxymethylcellulose (Sodium CMC), ethylcellulose, xanthan gum,
guar gum, acrylic acid derivatives, polyvinyl acetate, polyethylene
oxide and the likes known to those in the art. The release
retarding agents may be added in the range of 0.5 to 50% of total
weight of the composition of layer B
[0041] Disintegrants when used in the pharmaceutical composition
swells upon contact with the aqueous media and burst release of the
drug is observed. Disintegrating agents used in the present
composition maybe selected cross-linked polyvinyl pyrrolidone,
sodium starch glycolate or cross-linked sodium carboxy
methylcellulose, microcrystalline cellulose, starch, pregelatined
starch and the likes, preferably cross-linked sodium
carboxymethylcellulose is used. The disintegrating agent may be
present in an amount from 0.1 to 20%, preferably from 0.2 to 10%
and more preferably from 0.5 to 5%, by weight of the total weight
of the composition of layer B (w/w).
[0042] Pharmaceutical lubricants used in the present invention
maybe selected from stearic acid, magnesium streate, zinc stearate
and the like, silicone dioxide, hydrogenated vegetable oils,
glyceryl behenate, glyceryl monosterate, talc and the like. In the
present invention, the amount of lubricant used may be in the range
from about 0.1 to 5% and more preferably in the range of 0.1 to 3%
by weight of the total weight of the composition.
[0043] The binders used is selected from natural polymers selected
from starch or gum including acacia, tragacanth, gelatin or
synthetic polymers selected from polyvinyl pyrrolidone,
methylcellulose, ethylcellulose, hydroxypropyl methylcellulose,
sodium carboxymethylcellulose, hydroxypropyl cellulose.
[0044] The filler used in the present invention may be lactose,
mannitol, starch, pregelatinized starch, cellulose and the likes.
The concentration of the fillers in the present invention may vary
from about 2 to 80% of the total weight of the composition of the
layer B.
[0045] The pharmaceutical dosage form upon oral administration
floats on the surface of the gastric content based on the principle
of buoyancy due to hydrodynamically balancing property of the low
density polymers (Layer-A) and releases the drug in a controlled
fashion from the other layer (layer B) by diffusion and/or erosion
mechanism for a prolonged period.
Process for Preparation
[0046] According to the present invention the pharmaceutical dosage
form contains two layers, one responsible for the buoyancy (Layer
A) and other being the drug layer in the form of a matrix system
(Layer B). In the present invention, the granules for the two
different layers are prepared separately and then compressed into
bilayered tablet or caplet with suitable punch using suitable
tablet compression machine.
[0047] According to the present invention, the buoyant layer (Layer
A) can be prepared by physical mixing of the suitable excipients
mentioned above and can be compressed directly along with Layer-B.
Alternatively, the granules can also be prepared by hot melt
granulation or wet granulation technique using the suitable mixture
of above mentioned ingredients to obtain suitable size
granules.
[0048] According to the present invention, the granules of the drug
layer (Layer B) can be prepared by direct compression, dry
granulation or by wet granulation technique. In case of wet
granulation, the drug with release retarding polymers, optionally
with fillers, disintegrating agent was converted into dough mass
using binder in a particular solvent. The mass was sieved and
dried. The dried mass was sieved through ASTM #20. These granules
are then mixed with the lubricants and compressed into tablets
along with granules of Layer A.
[0049] Coating Process
[0050] The present invention relating to a buoyant pharmaceutical
composition and a method to prepare it in the form of tablets as
described above may be optionally coated with rapidly dissolving
water-soluble pharmaceutical excipients to mask the bitter taste of
the drug and/or to protect the dosage form from degradation during
varying storage conditions. A coating of low viscosity hydrophilic
polymer is preferred for the faster hydration and release of the
drug.
[0051] The film former can be cellulose derivatives including
hydroxypropyl methylcellulose, ethylcellulose and the like. Highly
water-soluble pharmaceutical excipients can be included in the
coating to support the faster dissolution of the polymer. The
water-soluble ingredient includes lactose, sucrose and the like.
The solvent used for the coating solution in the present invention
may be water, isopropyl alcohol or methylene chloride and mixture
of the same. The tablet may be coated to a weight gain of 0.5% to
8%, preferably 1% to 5%.
[0052] Following non-limiting example describe the illustrative
pharmaceutical compositions of the present invention and the means
of carrying out the invention to obtain a pharmaceutical dosage
form of various active agents for oral controlled release.
EXAMPLE-1
[0053] TABLE-US-00001 TABLE 1 Ingredients Mg/tab Layer-A Ethyl
cellulose 172 Hydrogenated castor oil 116 Mg. Stearate 6 Talc 6
Total weight 300 Layer B Ofloxacin 800 HPMC-K15 55.5 Cross-linked
sod CMC 23 PVP-K 90 27 Isopropyl alcohol q.s. Magnesium stearate
9.25 Talc 9.25 Total weight 1224
Layer A
[0054] Ethylcellulose and hydrogenated castor oil are mixed
together and the blend was heated on a controlled temperature water
bath at 90.degree. C. to obtain a congealed mass. The congealed
mass was cooled to room temperature and sieved through ASTM sieve
20. The blend was then lubricated.
Layer B
[0055] All the ingredients used in the formulation were passed
through a sieve (ASTM # 60). Ofloxacin, HPMC and cross-linked
sodium carboxymethylcellulose were mixed together with
polyvinylpyrrolidone (PVP) as a binder. The mass was dried and
passed through a sieve (ASTM #20). Tablets were prepared using
granules of Layer A and Layer B using a rotary bilayer tablet
compression machine using suitable punch. The tablets were spray
coated with hydroxypropyl methylcellulose (HPMC, 6 cps) to obtain
the weight gain in the range of 2-4%.
[0056] Dissolution study of the coated tablets was conducted in
0.1N HCl using USP Apparatus 1 (basket) at 100 rpm. The dissolution
results are given in Table-2 TABLE-US-00002 TABLE 2 Time (hr) %
drug release 1 33.0 2 57.2 3 73.19 4 90.03 5 96.5
EXAMPLE-2
[0057] TABLE-US-00003 TABLE 3 Ingredients Mg/tab Layer-A Ethyl
cellulose 90 Hydrogenated castor oil 60 Mg. Stearate 3 Talc 3 Total
weight 156 Layer B Ciprofloxacin 500 HPMC-K15 40 Cross-linked
sodium CMC 15 PVP-K 90 18 Isopropyl alcohol q.s. Magnesium stearate
4 Talc 4 Total weight 737
Layer A
[0058] Ethylcellulose and hydrogenated castor oil are mixed
together and the blend was lubricated.
Layer B
[0059] All the ingredients used in the formulation were passed
through a sieve (ASTM # 60). Ciprofloxacin, HPMC and cross-linked
sodium carboxymethylcellulose were mixed together with
polyvinylpyrrolidone (PVP) as a binder. The mass was dried and
passed through a sieve (ASTM #20). Tablets were prepared using
rotary bilayer tablet compression machine with suitable punch. The
tablets were spray coated to obtain the weight gain in the range of
2-4%.
[0060] Dissolution study of the coated tablets was conducted in
0.1N HCl using USP Apparatus 1 (basket) at 100 rpm. The dissolution
results are given in Table-4 TABLE-US-00004 TABLE 4 Time (hr) %
drug release 1 41.50 2 60.48 4 85.01 6 96.246
EXAMPLE-3
[0061] TABLE-US-00005 TABLE 5 Ingredients Mg/tab Layer-A Ethyl
cellulose 85 Hydrogenated castor oil 45 Mg. Stearate 3 Talc 3 Total
weight 136 Layer B Acyclovir 525 HPMC-K15 60 Cross-linked sod CMC
80 PVP-K 90 8 Isopropyl alcohol q.s. Magnesium stearate 8 Talc 7
Total weight 824
Layer A
[0062] Ethylcellulose and hydrogenated castor oil are mixed
together and the blend was lubricated.
Layer B
[0063] All the ingredients used in the formulation were passed
through a sieve (ASTM # 60). Acyclovir, HPMC and cross-linked
sodium carboxy methylcellulose were mixed together with
polyvinylpyrrolidone (PVP) as a binder. The mass was dried and
passed through a sieve (ASTM # 20). Tablets were prepared using
rotary bilayer tablet compression machine with suitable punch. The
tablets were spray coated to obtain the weight gain in the range of
2-4%.
[0064] Dissolution study of the coated tablets was conducted in
0.1N HCl using USP Apparatus 1 (basket) at 100 rpm. The dissolution
results are given in Table-6 TABLE-US-00006 TABLE 6 Time (hr) %
drug release 1 24.0 2 33.0 4 43.02 6 55.82
Advantages of the present invention: [0065] 1. The present
invention provides combined benefit of providing spatial control
(targeted drug release) and temporal control (prolonged drug
release) [0066] 2. There is no lag time for floating of the
composition prepared according to the present invention. [0067] 3.
The present invention does not require the use of gas generating
components for providing the floating characteristics. [0068] 4.
The composition of the present invention can be administered to the
patients suffering from achlorhydria. [0069] 5. The operational
simplicity and cost effectiveness of the present invention makes it
suitable for industrial application. [0070] 6. It is possible to
modify the floating characteristics by manipulating the shape and
size of the dosage form.
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